“This is the peer reviewed version of the following article: Chem. Eur. J. 2016, 22, 18247–18253, which has been published in
final form at http://onlinelibrary.wiley.com/doi/10.1002/chem.201604048/abstract . This article may be used for non-commercial purposes in
accordance with http://olabout.wiley.com/WileyCDA/Section/id-820227.html .“


Key non-metal ingredients for Cu-catalyzed “Click” reactions in
glycerol: nanoparticles as efficient forwarders
Marta Rodríguez-Rodríguez,[a,b] Patricia Llanes,[b] Christian Pradel,[a] Miquel A. Pericàs*[b] and
Montserrat Gómez*[a]
Abstract: The effect of long-alkyl chain amines in CuI-assisted azide-alkyne cycloadditions of terminal alkynes with organic azides in glycerol
and other eco-friendly solvents (water, ethanol) has been examined. The presence of these additives favors the in situ formation of Cu(I)-based
nanoparticles and results in an increase of reactivity. In glycerol, liquid phase Transmission Electron Microscopy (TEM) analyses enabled by
the negligible vapor pressure of this solvent proved that Cu(I) nanoparticles are responsible of the observed catalytic activity. The wide variety
of alkynes and azides where this effect has been investigated (14 combinations) confirms the role played by these additives in Cu-catalysed
Huisgen cycloadditions.

Introduction
Copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions represents a succeeding method for the synthesis of 1,2,3-triazoles,[1]
as itemized by the thousands of works published in this field,[2a] including enantioselective CuAAC transformations.[2b-c] This remarkable
success is mainly due to the process versatility in terms of solvent compatibility, copper sources (salts, well-defined complexes,
preformed nanoparticles, (un)supported systems), functional group tolerance and energy supplies (conventional heating, microwave
activation) among others. However, this hands-on behavior leads to some concerns from an understanding point of view (“who does
what”), associated to the lack of concluding studies in relation to CuAAC mechanism(s),[3] in particular for in situ generated systems
using Cu(I) starting materials. The most used precursors, copper halides, are quite insoluble in the common organic solvents, especially
CuI.[4] The presence of any additive (impurity) can improve the solubility of copper species in the medium, inducing then an increase of
catalytic activity. In this context, organic bases play a decisive task, favoring both the coordination to metal (as Lewis bases) and the
formation of active intermediates such as copper acetylides. Particularly, polydentate nitrogen-based ligands have been proved as
efficient copper partners, stabilizing Cu(I) species[5]and enhancing the rate of CuAAC processes.[6] In this frame, Cu(I) complexes
containing tris-(triazolyl)methane tripodal ligands, which are highly proficient in CuAAC reactions,[1f, 7] represent an elegant approach
to illustrate the role of Lewis bases (Chart 1). These ligands can efficiently stabilize catalytic precursors (I) and also intermediates acting
as hemi-labile scaffolds (II), which generates vacant sites for the coordination of reagents (Chart 1).

Chart 1. Tris(triazolyl)methane ligands for Cu(I)-catalysed AAC.

[1f, 7]

Small square denotes vacant site on copper.

In agreement with these important, ancillary tasks, base-free catalytic CuAAC systems are rare using Cu(I) complexes as copper
source. To the best of our knowledge, only one recent publication by García-Alvarez and Vidal reports on a Cu(I) system able to
catalyze CuAAC reactions in glycerol in the absence of any added base.[8]
Following our work on the use of glycerol as a solvent in
metal-catalyzed processes[9] and more recently in metal-free AAC
[a]
Ms. Marta Rodríguez, Mr. Christian Pradel, Prof. Montserrat Gómez
for the synthesis of fully substituted 1,2,3-triazoles,[10] where the
Laboratoire Hétérochimie Fondamentale et Appliquée (LHFA)
activation of both alkynes and benzylazide by glycerol was proved,
Université de Toulouse, UPS and CNRS UMR 5069
we planned to evaluate the activity of Cu(I) salts towards click
118, route de Narbonne, 31062 Toulouse cedex 9 (France)
reactions in this solvent, with the aim of understanding the role of
E-mail: gomez@chimie.ups-tlse.fr
[b]
Ms. Marta Rodríguez, Dr. Patricia Llanes, Prof. Miquel A. Pericàs
added exogenous base in glycerol medium.
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona
Institute of Science and Technology
Avda. Països Catalans, 16, 43007 Tarragona (Spain)
E-mail: mapericas@iciq.es

Supporting information for this article is given via a link at the end of
the document.

Results and Discussion
We selected the cycloaddition between phenylacetylene and benzyl azide as the benchmark reaction, using CuI as catalyst source in
neat glycerol at room temperature (Scheme of Table 1). The reaction did not work at all at short reaction times (1.5 h), 84% conversion
being achieved after 24 h (entry 1, Table 1). In the course of our researchers, it was reported the high efficiency of this methodology
under exactly the same “base-free” reaction conditions, triazole 1a being isolated by these authors in 94% yield in short reaction times.[8]
This serious discrepancy between independent runs of an easy-to-perform process, almost fulfilling the requirements in the Cornforth
definition of an ideal chemical process[11] led us to think that some uncontrolled factor was operating. Given the practical importance of
azide-alkyne cycloadditions, we decided to deeply characterize the different components involved in the process in an attempt to
rationalize this behavior.[12] This analytical study showed that the reaction worked or not depending on the quality (source) of BnN3
(entries 2-4, Table 1) and that, rather surprisingly, high-purity samples of azide were unreactive. In fact only one commercially available
lot of BnN3 favored the cycloaddition (entry 2, Table 1).
We analyzed the “active” BnN3 by GC-MS and NMR (Figs. S1-S3 in the Supplementary Information). In contrast to the other BnN3
samples (Figs. S4-S9 in the Supplementary Information), this one was contaminated by some compounds which, according to MS,
appeared to correspond to amines containing long-alkyl chains. To test the possible catalytic effect of these impurities, we carried out
the cycloaddition in the presence of amines using high purity, home-made BnN3 (Table 2). We observed that using 5 mol% of amine
with respect to benzyl azide, primary (entries 1-3, Table 2), secondary (entry 4, Table 2) and tertiary (entry 5, Table 2) long-alkyl chainbased mono-amines led to high yields of the corresponding 1,2,3-triazole, 1a. For short-alkyl chain derivatives, such as triethylamine
or diisopropylethylamine, low yields were achieved (<16%, entries 6-7, Table 2). When the amount of added amine decreased (1 mol%),
the reaction also worked (entries 1 and 3-5, Table 2), especially for oleylamine, dioctyl and trioctyl amine (entries 3-5, Table 2).
Ammonium salts, such as trioctylmethylammonium chloride (TOMACl) and Aliquat®336 (ammonium salt containing a mixture of C8 and
C10 alkyl chains, often used as a metal extraction reagent[13]), did not favor the cycloaddition (entries 8-9, Table 2).
Table 1. Azide-alkyne cycloaddition of phenylacetylene and benzyl
[a]
azide in the presence of CuI.

Entry

1

[d]

Bn-N3
[b]
Source/Batch code

Conv. (yield)
[c]
(%)

Home-made

<5
[e]
84 (69)
[f]

2

Alfa-Aesar/C25Z013

100 (80)

3

Alfa-Aesar/AE040501

<5

4

Aldrich/BCBL4667V

<5

[a] Reaction conditions: CuI (1 mol%), benzyl azide (0.5 mmol) and
phenylacetylene (0.5 mmol) in glycerol (0.5 mL) at 25 °C for 1.5 h. [b]
For certificates of analyses, see Supplementary Information. [c]
1
Determined by H NMR analysis using 2-methoxynaphthalene as
internal standard; conversions based on BnN3. [d] For BnN3 synthesis,
see reference [24]. [e] In italics, data after 24 h reaction. [f] Data coming
from two different commercial flasks.

Dinitrogenated (EN, o-PDA and PHEN, entries 11-13, Table 2) and tetranitrogenated (urotropine) ligands (entry 14, Table 2) did
not trigger a positive outcome (yields <12%). TMEDA was an exception to this behavior (70% yield, entry 10, Table 2). The use of 2,6lutidine, known by its performance in CuAAC in aqueous medium,[14] gave very low yield (entry 15, Table 2).
The same trend could be found when phenyl azide was used instead of benzyl azide (entries 16-24, Table 2): the system was
inactive in the absence of an added amine (entry 16, Table 2). While high isolated yields were recorded in the presence of amines
containing a long-alkyl chain (up to 94%, entries 17-20, Table 2). For “light” amines (entries 21-24, Table 2), only CuI/TMEDA system
was active as observed with BnN3 (entries 10 and 22, Table 2).
Furthermore, this “magic” amine effect was examined in other polar solvents, such as water, ethanol or 1,4-dioxane. Under the
same conditions than described above, the behavior was comparable to that observed in glycerol. In the absence of any additive or in
the presence of NEt3, low yields were obtained (<13%, entries 1-6, Table 3). However in the presence of dioctylamine (entries 7-9,
Table 3) or oleylamine (entries 10-12, Table 3), the increase of catalytic activity was clearly apparent.
It is important to mention that the catalytic phase could be recycled up to four times without significant loss of efficiency (entry 3,
Table 2; see Fig. S10 in the Supporting Information), showing the ability of glycerol to immobilize the catalyst. The dramatic effect
observed after the fourth run is undoubtedly related to the leaching of copper (more than 1,000 ppm determined by ICP-MS).

Table 2. Azide-alkyne cycloaddition of phenylacetylene
[a,b]
corresponding azide in the presence of CuI and amine.

and

Entry

Azide

Amine

Product,
[b]
Conv. (yield) (%)

1

a

NH2(octyl)

1a, 96 (93)
[c]
52 (44)

2

a

NH2(undecyl)

1a, 96 (93)

3

a

Oleylamine

1a, 100 (>99)
[c]
98 (94)
[d]
Run 4: 100 (85)

4

a

NH(octyl)2

1a, 100 (96)
[c]
95 (88)

5

a

N(octyl)3

1a, 96 (88)
[c]
97 (73)

6

a

NEt3

1a, 28 (16)

7

a

NEt(iPr)2

1a, 36 (6)

8

a

TOMACl

1a, 37 (19)

[e]

a

Aliquat 336

®

1a, 20 (<5)

10

a

TMEDA

1a, 83 (70)

11

a

EN

1a, 30 (12)

12

a

o-PDA

1a, 30 (10)

13

a

PHEN

1a, 15 (6)

14

a

Urotropine

1a, 20(<5)

15

a

2,6-lutidine

1a, 34(26)

16

b

-

1b, <5

17

b

NH2(octyl)

1b, 100 (94)
[c]
39 (9)

18

b

Oleylamine

1b, 100 (98)
[c]
100 (87)

19

b

NH(octyl)2

1b, 83 (89)
[c]
88 (87)

20

b

N(octyl)3

1b, 88 (88)
[c]
100 (12)

21

b

NEt3

1b, 10 (6)

22

b

TMEDA

1b, 70 (76)

23

b

EN

1b, 21 (19)

9

the

24

b

Urotropine

1b, <5

[a] Reaction conditions: CuI (1 mol%), amine (5 mol%), benzyl or phenyl azide
(0.5 mmol) and phenylacetylene (0.5 mmol) in glycerol (0.5 mL) at 25 °C for
1
1.5 h. [b] Determined by H NMR analysis using 2-methoxynaphthalene or
1,3,5-trimethoxybenzene as internal standard; conversions based on BnN3.
[c] In italics, conversion (yield) using 1 mol% of amine. [d] See Fig. S10 for
®
the recycling of the catalytic phase. [e] Aliquat 336: ammonium salts
containing a mixture of C8 and C10 alkyl chains with C8 predominating.

With these results in hand, a representative set of Cu-catalyzed azide-alkyne cycloadditions involving the use of different alkynes
(1-10) and organo-azides (a, b) (Fig. 1) was carried out in the presence of oleylamine. The corresponding triazoles were obtained in
high to quantitative yield. Even those triazoles bearing alkyl substituents at C-4 (3a, 7a, 7b) were obtained in moderate-to-high yields
(53-91%). No transesterification reactions with glycerol were detected for alkynes containing ester groups (2a, 4a). For selected
triazoles, the reactions were also carried out in the absence of added amine, as control experiments. In all cases, low yields (<25%,
see Table S1 in the Supplementary information) were recorded even at longer times (up to 7h). Unfortunately, this catalytic system,
working under smooth conditions, was not active using internal alkynes, such as diphenylacetylene or those more activated, methyl
phenylpropiolate or 1-iodo-2-phenylacetylene (Fig. S11 in the Supporting Information).
With the aim of understanding the observed reactivity, we analyzed the structural behavior of copper salts. From a coordination
point of view, the CuI motif leads to a large variety of structures corresponding to both discrete molecular complexes[15] and polymeric
networks,[16] depending on the nature of the ligands involved and also the reaction conditions. This structural variety is especially
remarkable when N-based ligands are involved,[17] in particular for diamines (EN, TMEDA, PHEN) and short-alkyl chain tertiary amines
(NEt3, NEtiPr2) like those used in this work.[18] Some of them give complex structures based on closed-cubane “Cu4I4“ tetramers;[18a,19]
we could prove this trend by the X-ray diffraction analysis of Cu4I4-TMEDA system (Figs. S12-S13 in the Supporting Information).[20]
Table 3. Azide-alkyne cycloaddition of phenylacetylene and benzyl azide in
[a]
the presence of CuI and amine.

Entry

Solvent

Amine

Conv. (yield) (%)

1

H2 O

-

22 (13)

2

EtOH

-

12 (<5)

3

Dioxane

-

11 (<5)

4

H2 O

NEt3

15 (<5)

5

EtOH

NEt3

17 (<5)

6

Dioxane

NEt3

24 (11)

7

H2 O

NH(octyl)2

100 (93)

8

EtOH

NH(octyl)2

66 (48)

9

Dioxane

NH(octyl)2

100 (99)

10

H2 O

Oleylamine

99 (94)

11

EtOH

Oleylamine

59 (48)

12

Dioxane

Oleylamine

[b]

94 (81)

[a] Reaction conditions: CuI (1 mol%), amine (5 mol%), benzyl or phenyl azide
(0.5 mmol) and phenylacetylene (0.5 mmol) in the appropriate solvent (0.5
mL) at 25 °C for 1.5 h. Triazole 1a was not obtained in the absence of copper
1
(18% conversion, <5% yield for 1a). [b] Determined by H NMR analysis using
2-methoxynaphthalene or 1,3,5-trimethoxybenzene as internal standard;
conversions based on BnN3.

In contrast, long-alkyl chain amines favor the stabilization of metal (and metal oxide) nanoparticles.[21] Presuming the formation
of copper-based nanoclusters under our reaction conditions,[22] TEM analyses of CuI in glycerol and in the presence of different amines
were carried out (Table S2 in the Supporting Information). Actually, the formation of well-dispersed nanoparticles was observed in the
presence of long-alkyl chain amines, including ammonium derivatives (Fig. 2). HR-TEM and EDX analyses of CuI/dioctylamine mixture

in glycerol confirmed the Cu(I) nature of the nanoparticles and the presence of the amine on the nanoparticles surface (Fig. S14 in the
Supporting Information). It is worth noting that ammonium salts such as TOMACl and Aliquat®336 did not lead to catalytically active
systems, although the formation of well-dispersed nanoparticles was also observed. The lack of catalytic activity in these last cases is
probably due to the very strong electrostatic interaction between the ionic ligands and the nanoparticles: Cu(I)-based nanoparticles are
now tightly surrounded by anion/cation shells, and this leads to small and well-dispersed particles. However, this stabilizing interaction
shields the nanoparticles surface and prevents the requisite approach of the reactants to the catalytic copper centers. By the contrary,
hemi-labile amine ligands while still preventing particle agglomeration by steric shielding, can be easily detached leading to free
coordination sites on copper for the reaction to proceed.[23]

Figure 1. Scope of azide-alkyne cycloaddition catalysed by CuI/amine system in glycerol. Figures indicate isolated yields.

Interestingly, the presence of additional ionic compounds in the reaction medium could be shown to be not innocent. Thus, when
an equimolar mixture of Aliquat®336 and a sodium salt (NaOAc or NaN3) was added to the non-productive reaction mixture, the system
turned into active (Fig. 3). TEM analyses of CuI in glycerol in the presence of both Aliquat®336 and sodium salt evidenced the formation
of micelle-like arrangements, giving high local density of copper and therefore favoring the reactivity. This effect can be specially
observed in the case of the mixture Aliquat®336/NaOAc, where cylindrical micelles were identified, containing the copper species at
the surface (accessible to the reagents) and the more hydrophobic constituents (ammonium alkyl species) probably placed inside of
these nano-objects. A similar trend could be observed using TOMACl/NaN3 (Fig. S15 in the Supporting Information). It is important to
note that CuI/NaN3 and CuI/NaOAc systems (in the absence of any nitrogen-based ligand) were not active. In addition, this reactivity
behavior points to the feasibility of CuAAC by one-pot three-component approach. Actually, using as starting materials Bn-Br, NaN3
and phenylacetylene, 1a was obtained in 90% isolated yield (see Scheme S1 in the Supporting Information)
Correlating reactivity and structures, it seems that the formation of nanoparticles favors the catalytic process, what points to a
beneficial (cooperative) effect between neighboring Cu(I) centers for the activation of both azide and alkyne reactants during the
cycloaddition, as already noted in our previous work involving the use of Cu2O nanoparticles as catalytic precursors in glycerol
medium.[9a]

Figure 2. TEM images for CuI-based systems containing oleylamine (a), dioctylamine (b) and TOMACl (c) in glycerol.

In fact, for short-chain alkyl amines such as DIPEA, ethylenediamine or urotropine, agglomerates similar to those observed for
CuI in the absence of any additive, were formed (Table S2 in the Supporting Information), affording inactive catalytic systems (Table

2). Only CuI/TMEDA led to the simultaneous formation of nanoparticles and agglomerates. As we have already mentioned, this system
depicted high catalytic activity in azide-alkyne cycloadditions (entries 10 and 22, Table 2).

®

Figure 3. Effect of the salts in azide-alkyne cycloaddition. TEM images corresponding to the mixtures of CuI, Aliquat 336 and NaX (1/5/5 ratio, respectively): NaOAc
(left), including an inserted image of one of the cylindrical micelle-like objects; NaN3 (right).

We were also interested in establishing the oxidation state of copper involved in the active species. For that, we reused the
catalytic phase corresponding to the active CuI/dioctylamine system (after reaction between phenylacetylene and benzyl azide); TEM
analysis after catalysis showed smaller nanoparticles than before (ca. 1.4 nm (after) vs 2.1 nm (before); Table S2 in the Supporting
Information); the catalytic phase was then much less active (33% in the second run vs 100% in the first one). HR-TEM coupled to an
electronic diffraction analysis showed that particles after the first catalytic run were mainly constituted by Cu(0) (Fig. S16 in the
Supporting Information). This indicate us that the initially formed Cu(I)-rich nanoparticles suffer reductive deactivation as a concomitant
off-cycle of CuAAC reaction In contrast, the reutilization of CuI/oleylamine system gave the same activity than for the first run (for both
cases, nearly full conversion); HR-TEM/electronic diffraction analysis proved that nanoparticles were in this case mainly formed by
Cu(I) after catalysis (Fig. S17 in the Supporting Information). In addition, XPS analyses evidenced the absence of Cu(II) species after
reaction (absence of the corresponding strong satellites) (see Fig. S18 in the Supporting Information). These data point to Cu(I)-based
nanoparticles as responsible of the reactivity observed.

Conclusions
In this work, we could prove the key role of “impurities” randomly present in commercial samples of benzyl azide. Its accurate
analyses led us to identify them (long-alkyl chain amines) and to examine their impact on CuI-based catalytic systems applied in azidealkyne cycloadditions in different solvents. As a practical result of this study, we have been able to establish that the addition of small
amounts (5 mol%) of primary, secondary and tertiary amines containing C8, C11 and C18 carbon chains (CuI/amine ratio = 1/1 or 1/5)
secures the success in the synthesis of 1,4-disubstituted 1,2,3-triazoles under mild reaction conditions (low metal loading -1 mol%-,
short time -1.5 h- and room temperature), in eco-friendly glycerol. As a corollary, a warning should be made on experimental procedures
for CuAAC reaction in polar solvents not involving the use of appropriate amines: Their success or failure hardly depends on the
presence/absence of amine-type impurities in the employed azide. The use of glycerol as a non-volatile solvent enabled the analyses
of solutions constituted by CuI and amine, before and after catalysis, by (HR)TEM. It could be learned from these studies that CuI, in
the presence of long-alkyl chain amines in glycerol at room temperature, gives raise to the formation of small and well-dispersed Cu(I)
nanoparticles, in contrast with the agglomerates formed from either bulk CuI or from mixtures of CuI with low-weight amines. It is
important to mention that the presence of ammonium salts mainly containing C8 chains (TOMACl, Aliquat® 336) did not give an efficient
catalytic system in spite of the formation of well-dispersed nanoparticles, almost certainly caused by the stabilization of CuI
nanoparticles by electrostatic effect, blocking the access of reagents to the Cu(I) centers. However tuning the ionic species present in
the reaction medium, the catalytic system turned into active through the formation of organized systems.
Altogether, this study led us to establish a correlation between the in situ formation of Cu(I) nanoparticles in glycerol and other
polar solvents and their catalytic activity. These nano-objects, generated thanks to the presence of long-alkyl chain amines, favor the
activation of both reagents, alkyne and azide partners, by cooperative effect between neighboring Cu(I) centers.
The inconsistencies found working under the “same” conditions induce the desire to understand, discovering new issues for
known reactions. The use of controlled-quality compounds (reagents, catalysts, solvents) permits to dramatically reduce the casual
effects, establishing reproducible and sustainable protocols.

Experimental Section
General procedure for the azide-alkyne cycloaddition. CuI (0.9 mg, 0.005 mmol) and the corresponding amine (0.005 – 0.25 mmol) were added to
0.5 mL of glycerol in a Schlenck tube equipped with a stirring bar under Ar atmosphere. The alkyne (0.5 mmol) and the azide (0.5 mmol: 67 mg for
BnN3[24] and 60 mg for PhN3) were added consecutively to the reaction medium. The mixture was stirred at 25 °C for 1.5 h (or the stated time). The
organic products were extracted from the catalytic mixture with dichloromethane (6 x 2 mL). The combined chlorinated organic layers were filtered through
a Celite® pad and the resulting filtrate was concentrated under reduced pressure. The products were purified by chromatography (silica gel short column,
eluent: cyclohexane/ethyl acetate) in order to determine the isolated yields of the corresponding triazoles.

Acknowledgements
Financial support from the Centre National de la Recherche Scientifique (CNRS), the Université de Toulouse 3 - Paul Sabatier, MINECO
(grants CTQ2012–38594-C02–01 and CTQ2015-69136-R), DEC (grant 2014SGR827) and ICIQ Foundation are gratefully
acknowledged. S. Ladeira and R. Brousses are acknowledged for the resolution of the XRD structure. M. R. thanks the CNRS and
MINECO (CTQ2012-38594-C02-01) for a PhD grant.
Keywords: azide-alkyne cycloaddition • copper • nanoparticles • long-chain amines • glycerol
[1]

[2]

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[7]
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[12]
[13]
[14]
[15]
[16]
[17]
[18]

[19]
[20]
[21]

[22]
[23]
[24]

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Entry for the Table of Contents

FULL PAPER
Marta Rodríguez-Rodríguez, Patricia
Llanes, C. Pradel, Miquel A. Pericàs*
and Montserrat Gómez*
Page No. – Page No.

The noteworthy reactivity observed in CuAAC reactions, using CuI in the presence
of long-chain amines as starting catalytic materials, could be correlated to the in situ
formation of Cu(I) nanoparticles. These amines, acting as “magic” ingredients,
become crucial for accelerating the process, in particular in glycerol medium.

Key non-metal ingredients for Cucatalyzed “Click” reactions in
glycerol: nanoparticles as efficient
forwarders